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2.
Int Immunopharmacol ; 81: 106261, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32058928

RESUMO

Exacerbation of chronic obstructive pulmonary disease (COPD) is characterized by acute airway inflammation and mucus hypersecretion, which is by far the most costly aspect of its management. Thus, it is essential to develop therapeutics with low side effects for CODP exacerbation. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA isolated as the major active component of Chinese herbal medicine Danshen. Although it possesses anti-inflammatory, anti-oxidative and anti-apoptotic properties, it remains unknown whether STS protects against COPD exacerbation. In this study, we challenged cigarette smoke (CS)-exposed mice with lipopolysaccharide (LPS), and then treated these mice with STS. We found that STS significantly ameliorated pulmonary inflammatory responses, mucus hypersecretion and lung function decline in CS-exposed mice challenged with LPS. STS treatment also significantly attenuated increased IL-6 and IL-8 releases from cigarette smoke extract (CSE)-treated human bronchial epithelial cells (16HBE) challenged with LPS. Mechanistically, STS reduced activation of ERK1/2 and NF-κB in lungs of CS-exposed mice and CSE-treated 16HBE cells challenged with LPS. Taken together, STS protects against acute exacerbation of CS-induced lung injury, which provides a promising and potential therapeutic avenue to halt acute exacerbation of COPD.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31940248

RESUMO

Unlike the pulmonary artery (PA), the pathophysiological changes of the pulmonary vein (PV) in the development of pulmonary hypertension (PH) remain largely unknown. In this study, we comprehensively investigated the structural and functional changes in the PV isolated from the chronic hypoxia (CH, 10% O2, 21 days)-induced PH rat model (CHPH). Results showed that CH caused an increase in right ventricular pressure, but did not affect the mean pulmonary venous pressure and the left atrial pressure. Similar as the PA, vascular lumen stenosis and medial thickening were also observed in the intrapulmonary veins isolated from the CHPH rats. Notably, CH induced more severe loss in the endothelium of intrapulmonary veins than the arteries. Then, the contractile response to 5-HT and U46619 were significantly greater in the intrapulmonary small veins (ISPV) and arteries (ISPA) isolated from CHPH rats than those from normoxic rats, but not in the extrapulmonary large veins (ELPV) and intrapulmonary large veins (ILPV). Treatment with either nifedipine (Nif), SKF96365 (SKF) or ryanodine+caffeine either partially attenuated (Nif) or dramatically abolished (SKF or ryanodine+caffeine) 5-HT-induced maximal contraction in ISPV from both normoxic and CHPH rats. Due to the severe loss of endothelium in the PV of CHPH rats, the decrease in acetylcholine (ACh)-induced endothelium-dependent relaxation was significantly larger in ISPV than ISPA, while the sodium nitroprusside (SNP)-induced endothelium-independent relaxation was not altered in both ISPA and ISPV. In conclusion, our data provided fundamental data to comprehensively define the PV system in CHPH rat model.

4.
Br J Pharmacol ; 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31976548

RESUMO

RATIONALE: Tetramethylpyrazine (TMP) is a compound isolated from the traditional Chinese herb ligusticum and the fermented Japanese food natto. TMP can also be chemosynthesized in pharmacy and has long history of proven effects in the treatment of many cardiovascular diseases. OBJECTIVES: To evaluate the potential therapeutic role of TMP on pulmonary hypertension (PH) both in experimental animal models and in clinical patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). RESULTS: TMP (100 mg•kg-1 •d-1 ) not only prevented rats from developing experimental PH, but also ameliorated PH in three models of established PH: chronic hypoxia- (chronic-HPH), sugen/hypoxia- (SuHx-PH) or monocrotaline-(MCT-PH) induced PH. The therapeutic effect of TMP was likely due to its inhibition of intracellular calcium homeostasis in pulmonary arterial smooth muscle cells. In a small cohort of patients with PAH or CTEPH, oral administration of TMP (100 mg, t.i.d. for 16 weeks) significantly increased the 6-minute walk distance (6MWD, from 385±83 to 446±80 meters; p=0.04 vs baseline, p=0.001 vs control). The 1-minute heart rate recovery (HRR1) was also improved from 13±6 to 19±8 bpm (p=0.03 vs baseline, p=0.001 vs control). CONCLUSION: Our results suggest that TMP is potentially a novel, potential and inexpensive medication for treatment of PH. Clinical trial is registered with www.chictr.org.cn (ChiCTR-IPR-14005379).

5.
Am J Respir Cell Mol Biol ; 62(1): 49-60, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31211918

RESUMO

For decades, stem cell therapies for pulmonary hypertension (PH) have progressed from laboratory hypothesis to clinical practice. Promising preclinical investigations have laid both a theoretical and practical foundation for clinical application of mesenchymal stem cells (MSCs) for PH therapy. However, the underlying mechanisms are still poorly understood. We sought to study the effects and mechanisms of MSCs on the treatment of PH. For in vivo experiments, the transplanted GFP+ MSCs were traced at different time points in the lung tissue of a chronic hypoxia-induced PH (CHPH) rat model. The effects of MSCs on PH pathogenesis were evaluated in both CHPH and sugen hypoxia-induced PH models. For in vitro experiments, primary pulmonary microvascular endothelial cells were cultured and treated with the MSC conditioned medium. The specific markers of endothelial-to-mesenchymal transition (EndMT) and cell migration properties were measured. MSCs decreased pulmonary arterial pressure and ameliorated the collagen deposition, and reduced the thickening and muscularization in both CHPH and sugen hypoxia-induced PH rat models. Then, MSCs significantly attenuated the hypoxia-induced EndMT in both the lungs of PH models and primary cultured rat pulmonary microvascular endothelial cells, as reflected by increased mesenchymal cell markers (fibronectin 1 and vimentin) and decreased endothelial cell markers (vascular endothelial cadherin and platelet endothelial cell adhesion molecule-1). Moreover, MSCs also markedly inhibited the protein expression and degradation of hypoxia-inducible factor-2α, which is known to trigger EndMT progression. Our data suggest that MSCs successfully prevent PH by ameliorating pulmonary vascular remodeling, inflammation, and EndMT. Transplantation of MSCs could potentially be a powerful therapeutic approach against PH.

6.
Redox Biol ; 28: 101356, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704583

RESUMO

Airway remodeling is one of the characteristics for chronic obstructive pulmonary disease (COPD). The mechanism underlying airway remodeling is associated with epithelial-mesenchymal transition (EMT) in the small airways of smokers and patients with COPD. Sirtuin 1 (SIRT1) is able to reduce oxidative stress, and to modulate EMT. Here, we investigated the effects and mechanisms of hydrogen sulfide (H2S) on pulmonary EMT in vitro and in vivo. We found that H2S donor NaHS inhibited cigarette smoke (CS)-induced airway remodeling, EMT and collagen deposition in mouse lungs. In human bronchial epithelial 16HBE cells, NaHS treatment also reduced CS extract (CSE)-induced EMT, collagen deposition and oxidative stress. Mechanistically, NaHS upregulated SIRT1 expression, but inhibited activation of TGF-ß1/Smad3 signaling in vivo and in vitro. SIRT1 inhibition by a specific inhibitor EX527 significantly attenuated or abolished the ability of NaHS to reverse the CSE-induced oxidative stress. SIRT1 inhibition also abolished the protection of NaHS against CSE-induced EMT. Moreover, SIRT1 activation attenuated CSE-induced EMT by modifying TGF-ß1-mediated Smad3 transactivation. In conclusion, H2S prevented CS-induced airway remodeling in mice by reversing oxidative stress and EMT, which was partially ameliorated by SIRT1 activation. These findings suggest that H2S may have therapeutic potential for the prevention and treatment of COPD.

7.
Aging (Albany NY) ; 11(24): 11844-11864, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31881011

RESUMO

Hydrogen sulfide (H2S), an endogenous gaseous signal molecule, regulates many pathologies related to aging. Sirtuin 1 (SIRT1) has been shown to protect against mitochondrial dysfunction and other pathological processes, including premature senescence. This study was aimed to investigate whether and how H2S attenuates senescence and apoptosis of alveolar epithelial cells via a SIRT1-dependent mechanism. Our results showed that treatment with sodium hydrosulfide (NaHS), a donor of H2S, attenuated cigarette smoke extract (CSE)-induced oxidative stress, mitochondrial dysfunction, cellular senescence and apoptosis in A549 cells. This was associated with SIRT1 upregulation. SIRT1 activation by a pharmacological activator, SRT1720, attenuated CSE-induced oxidative stress and mitochondrial dysfunction in A549 cells. While SIRT1 inhibition by EX 527 or silencing by siRNA transfection significantly attenuated or abolished the ability of NaHS to reverse the CSE-induced oxidative stress, mitochondrial dysfunction and the imbalance of mitochondrial fusion and fission. Also, SIRT1 inhibition or silencing abolished the protection of NaHS against CSE-induced cellular senescence and apoptosis. In conclusion, H2S attenuates CSE-induced cellular senescence and apoptosis by improving mitochondrial function and reducing oxidative stress in alveolar epithelial cells in a SIRT1-dependent manner. These findings provide novel mechanisms underlying the protection of H2S against cigarette smoke-induced COPD.

8.
Trials ; 20(1): 725, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842950

RESUMO

BACKGROUND: Tetramethylpyrazine (TMP), an active ingredient in the traditional Chinese herbal medicine Rhizoma Chuanxiong, has been used clinically for the prevention and treatment of cardiovascular disease. The benefits of TMP are largely attributed to its anti-oxidative and vasodilative properties. However, the efficacy of TMP in the treatment of pulmonary hypertension (PH) is unknown. We hypothesized that TMP may have a therapeutic effect in patients with PH. METHODS/DESIGN: A randomized, single-blinded, clinical study with a TMP treatment group and a control group will be conducted to evaluate the efficacy and safety of TMP intervention in patients with PH. The recruitment target is 120 subjects meeting the following criteria: (i) at rest and at sea level, mean pulmonary artery pressure above 20 mmHg and pulmonary capillary wedge pressure below 15 mmHg; (ii) type 1 or 4 PH in the stable phase; (iii) age 15-70 years; (iv) 6-min walk distance between 100 and 450 m; (v) World Health Organization (WHO) functional classification of pulmonary hypertension of II, III, or IV. Subjects will be assigned randomly into two groups at a ratio of 1:2 (control:TMP). Both groups will receive routine treatment, and the treatment group will also receive oral TMP (100 mg) three times a day for 16 weeks. All patients will be followed up for 4, 8, 12, and 16 weeks; symptoms and patient compliance will be recorded. DISCUSSION: We aimed to determine the efficacy and safety of TMP for the treatment of PH. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR1800018664. Registered on 2 October 2018.

9.
Int Immunopharmacol ; : 105979, 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31771816

RESUMO

Chronic obstructive pulmonary fibrosis (COPD) is a chronic and fatal lung disease with few treatment options. Sodium hydrosulfide (NaHS), a donor of hydrogen sulfide (H2S), was found to alleviate cigarette smoke (CS)-induced emphysema in mice, however, the underlying mechanisms have not yet been clarified. In this study, we investigated its effects on COPD in a CS-induced mouse model in vivo and in cigarette smoke extract (CSE)-stimulated alveolar epithelial A549 cells in vitro. The results showed that NaHS not only relieved emphysema, but also improved pulmonary function in CS-exposed mice. NaHS significantly increased the expressions of tight junction proteins (i.e., ZO-1, Occludin and claudin-1), and reduced apoptosis and secretion of pro-inflammatory cytokines (i.e., TNF-α, IL-6 and IL-1ß) in CS-exposed mouse lungs and CSE-incubated A549 cells, indicating H2S inhibits CS-induced inflammation, injury and apoptosis in alveolar epithelial cells. NaHS also upregulated prolyl hydroxylase (PHD)2, and suppressed hypoxia-inducible factor (HIF)-1α expression in vivo and in vitro, suggesting H2S inhibits CS-induced activation of PHD2/HIF-1α axis. Moreover, NaHS inhibited CS-induced phosphorylation of ERK, JNK and p38 MAPK in vivo and in vitro, and treatment with their inhibitors reversed CSE-induced ZO-1 expression and inflammation in A549 cells. These results suggest that NaHS may prevent emphysema via the suppression of PHD2/HIF-1α/MAPK signaling pathway, and subsequently inhibition of inflammation, epithelial cell injury and apoptosis, and may be a novel strategy for the treatment of COPD.

10.
Biochem Biophys Res Commun ; 520(3): 580-585, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31623833

RESUMO

BACKGROUND: Diabetes is a strong risk factor of peripheral arterial disease (PAD), and also leads to impaired perfusion recovery in the ischemic limb, which eventually results in poor outcomes in PAD patients. Sodium Tanshinone IIA Sulfonate (STS), a monomer from herbs, has been shown to improve the outcomes in a variety of ischemic disease including myocardial infarction. However, the effects of STS treatment in PAD is not known. METHODS AND RESULTS: Unilateral femoral artery was ligated in mice as experimental PAD models, STS treatment improved perfusion recovery, increased capillary densities, decreased reactive oxygen species (ROS) level and microRNA-133a (miR-133a) expression in the ischemic hindlimb in diabetic mice; however, STS did not change perfusion recovery in non-diabetic C57BL/6 mice. Ischemic muscle tissue from diabetic mice was harvested 7 days after femoral ligation for biochemical test, STS resulted in reduced malondialdehyde (MDA), and increased GTP cyclohydrolase 1 (GCH1) and cyclic guanine monophosphate (cGMP) levels. In addition, STS treatment increased miR-133a expression in endothelial cells isolated from ischemic muscle tissue of diabetic mice. In endothelial cells cultured in high glucose medium, STS increased tube formation and nitric oxide (NO) production, and reduced cellular ROS level and miR-133a expression under simulated ischemic condition. In addition, GCH1 inhibitor or miR-133a overexpression using exogenous microRNA mimic blunted STS-induced angiogenic effects and ROS neutralization in cultured endothelial cells under hyperglycemic and hypoxic conditions. CONCLUSION: These findings demonstrate STS improves angiogenesis via inhibiting miR-133a expression and increasing GCH-1 protein levels in experimental PAD with diabetes.

12.
Life Sci ; 232: 116650, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302196

RESUMO

BACKGROUND: Inhalation of NO2 leads to a progressive airflow limitation and the development of emphysema-like lesions. We report on the efficacy of hydrogen sulfide (NaHS) for alleviating NO2-induced pulmonary impairment. METHODS: Sprague Dawley rats were exposed to 20 ppm NO2 for 6 h over six consecutive days for 75 days. At day 75, rats who had developed NO2-induced emphysema were then divided into sodium hydrosulfide (NaHS) administrated group, placebo (NaCl) group and spontaneous recovery group for about one month (days 76-105); Pulmonary function (PF) and hematological and biochemical indices were measured at days 14, 45, 75, and 105. RESULTS: NO2 exposure for 75 days was associated with a significant decrease in FEV100/FVC%, an increased in functional residual capacity (FRC), and histologic evidence of emphysema, moreover; NO2 exposure led to elevated triglyceride (TG), red blood cell (RBC), hemoglobin (HGB), and hematocrit (HCT) levels. Impaired rats treated with NaHS showed no further deterioration in PF compared to rats exposed to ambient air and elevated WBC, granulocyte and lymphocyte counts and HDL-C levels to rats given NaCl. CONCLUSIONS: NO2 exposure causes emphysema and a decline in PF in rats. NaHS could alleviate the PF decline as possible indicated by an elevation of HDL-C levels and leukocyte. NaHS has therapeutic potential for emphysema caused by air pollutant NO2.


Assuntos
Testes Hematológicos , Pulmão/efeitos dos fármacos , Dióxido de Nitrogênio/toxicidade , Sulfetos/administração & dosagem , Sulfetos/farmacologia , Administração por Inalação , Animais , Pulmão/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Testes de Função Respiratória
13.
Sci Rep ; 9(1): 7398, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31068652

RESUMO

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

14.
J AOAC Int ; 102(5): 1448-1454, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31088594

RESUMO

Background: The essential oil content of the water lily is extremely low; thus, finding a new method that can extract essential oil from water lilies with a high extraction rate and no residual organic solvents is essential. Objective: The optimal processing conditions for the ultrasound-enhanced subcritical fluid extraction of essential oil from Nymphaea alba var (red water lily) and the antioxidant activity of the essential oil in vitro are investigated to provide theoretical bases for identification and development. Methods: Single-factor experiments and orthogonal designs are performed to determine the effects of extraction conditions on essential oil yields. The chemical composition of essential oil is analyzed using GC-MS. Results: The optimum extraction parameters are established as follows: extraction temperature, 35°C; extraction time, 30 min/time for four times; ratio of material to liquid, 1:3; ultrasound power, 250 W/L; and ultrasonic frequency, 20 kHz. The extraction rate of essential oil is 0.315% under these conditions. Eleven components comprise more than 1% content. The main chemical constituents are 8-hexadecyne (31.04%) and 2,6,10-trimethyl-tetradecane (3.95%). The essential oil from N. alba var has an antioxidant activity in vitro; however, its antioxidant activity is weaker than that of butylated hydroxytoluene. Conclusions: Subcritical fluid is suitable for the extraction of essential oil from N. alba var, and the essential oil has a good antioxidant activity. Highlights: The essential oil content of N. alba var is 0.315%. Forty-seven chemical constituents are identified and isolated from N. alba var and analyzed by GC-MS.


Assuntos
Antioxidantes/química , Nymphaea/química , Óleos Voláteis/química , Óleos Vegetais/química , Extração em Fase Sólida/métodos , Antioxidantes/isolamento & purificação , Cromatografia Gasosa-Espectrometria de Massas , Óleos Voláteis/isolamento & purificação , Óleos Vegetais/isolamento & purificação , Ondas Ultrassônicas
16.
PLoS One ; 14(3): e0208687, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30893301

RESUMO

There is limited evidence linking the impacts of reduced air pollution on hospital admissions. The potential biological mechanisms are still not completely understood. This study examined the effects of mitigated ambient pollution on hospital admissions and inflammatory biomarker levels in chronic obstructive pulmonary disease (COPD) COPD patients. Daily hospital admissions were compared over 51 days associated with the Asian Games period (Nov 1-Dec 21, 2010) with the identical calendar dates of baseline years (2004-2009 and 2011-2013). A three-year cohort study was conducted with 36 COPD patient participants. The daily particulate matter (PM10) decreased from 65.86 µg/m3 during the baseline period to 62.63 µg/m3 during the Asian Games period; the daily NO2 level decreased from 51.33 µg/m3 to 42.63 µg/m3. Between the baseline period and the Asian Games, daily hospital admissions from non-accidental diseases decreased from 116 to 93, respectively; respiratory diseases decreased from 20 to 17, respectively; and cardiovascular diseases decreased from 11 to 9 during the Asian Games period, respectively. No statistically significant reductions were seen in the remaining months of 2010 in Guangzhou, during the the Asian Games period in the control city, and two other control diseases. Furthermore, we identified significant improvement in CRP and fibrinogen by -20.4% and -15.4% from a pre-Asian game period to a during-Asian game period, respectively. For CRP, we found significant increases in NO2 at lag1-3 days after-Asian game period and significant increases in PM10 at lag1-2 days. Similar effects were also seen with fibrinogen. This discovery provides support for efforts to diminish air pollution and improve public health through human air pollutants intervention. Improved air pollution during the 2010 Asian games was correlated with decreases in biomarkers associated with systemic inflammation in COPD patient participants.


Assuntos
Poluição do Ar/análise , Admissão do Paciente/estatística & dados numéricos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Adolescente , Adulto , Idoso , Poluentes Atmosféricos/análise , Criança , Pré-Escolar , China/epidemiologia , Estudos de Coortes , Biomarcadores Ambientais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Material Particulado/análise , Adulto Jovem
17.
Life Sci ; 221: 121-129, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30763575

RESUMO

AIMS: A rat model of emphysema was established that mimics the features of the human emphysema subtype and explores the effects of demethylation on lung function and blood tests. MATERIALS AND METHODS: Rats were randomly assigned to NO2, NO2 + 5-Azacytidine, and normal air groups based on a emphysema rat model induced by chronic NO2 exposure. This study estimates the characteristics of emphysema by conducting an analysis for IL-6 and TNF-α levels in bronchoalveolar lavage fluids (BALF) and plasma. Furthermore, CD68 macrophage immunofluorescent staining and inflammatory cell counts in BALF were compared between rats exposed to NO2 and normal air. KEY FINDINGS: 5-Azacytidine treatment led to restored ∆weight at 14 and 75 days of intervention and NO2 + 5-Azacytidine significantly reversed the effect of NO2 exposure on ∆weight. Intervention with 5-Azacytidine alleviated the decline of pulmonary function with a significant increase in FEV100/FVC% at 75 days in NO2 + 5-Azacytidine rats compared to NO2 rats. 5-Azacytidine reduced the counts of white blood cells (WBCs), granulocytes, lymphocytes, and monocytes at 14 days, but increased WBC, granulocyte, and monocyte counts at 45 days. Red blood cell counts, hemoglobin, and hematocrit concentrations were significantly reduced in NO2 + 5-Azacytidine rats. SIGNIFICANCE: This non-inflammatory rat emphysema model (induced by chronic NO2 exposure with global DNA hypomethylation and demethylation therapy with 5-Azacytidine) effectively improved emphysema by alleviating the decline of lung function and hypoxia, and slightly reinforced immune function. These results indicate the therapeutic potential of demethylation agents for the prevention and treatment of emphysema induced by the air pollutant NO2.


Assuntos
Azacitidina/metabolismo , Azacitidina/farmacologia , Enfisema/tratamento farmacológico , Animais , Líquido da Lavagem Broncoalveolar/citologia , Citocinas , Desmetilação/efeitos dos fármacos , Modelos Animais de Doenças , Enfisema/metabolismo , Enfisema/fisiopatologia , Interleucina-6/análise , Contagem de Leucócitos , Pulmão , Macrófagos , Masculino , Neutrófilos , Óxido Nítrico , Enfisema Pulmonar , Ratos , Ratos Sprague-Dawley , Testes de Função Respiratória/métodos , Fator de Necrose Tumoral alfa/análise
18.
Am J Physiol Lung Cell Mol Physiol ; 316(1): L216-L228, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30358436

RESUMO

The tumor-suppressive role of p53, a transcription factor that regulates the expression of many genes, has been linked to cell cycle arrest, apoptosis, and senescence. The noncanonical function or the pathogenic role of p53 has more recently been implicated in pulmonary vascular disease. We previously reported that rapid nuclear accumulation of hypoxia-inducible factor (HIF)-1α in pulmonary arterial smooth muscle cells (PASMCs) upregulates transient receptor potential channels and enhances Ca2+ entry to increase cytosolic Ca2+ concentration ([Ca2+]cyt). Also, we observed differences in HIF-1α/2α expression in PASMCs and pulmonary arterial endothelial cells (PAECs). Here we report that p53 is increased in PAECs, but decreased in PASMCs, isolated from mice with hypoxia-induced pulmonary hypertension (PH) and rats with monocrotaline (MCT)-induced PH (MCT-PH). The increased p53 in PAECs from rats with MCT-PH is associated with an increased ratio of Bax/Bcl-2, while the decreased p53 in PASMCs is associated with an increased HIF-1α. Furthermore, p53 is downregulated in PASMCs isolated from patients with idiopathic pulmonary arterial hypertension compared with PASMCs from normal subjects. Overexpression of p53 in normal PASMCs inhibits store-operated Ca2+ entry (SOCE) induced by passive depletion of intracellularly stored Ca2+ in the sarcoplasmic reticulum, while downregulation of p53 enhances SOCE. These data indicate that differentially regulated expression of p53 and HIF-1α/2α in PASMCs and PAECs and the cross talk between p53 and HIF-1α/2α in PASMCs and PAECs may play an important role in the development of PH via, at least in part, induction of PAEC apoptosis and PASMC proliferation.


Assuntos
Células Endoteliais/metabolismo , Hipertensão Pulmonar/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cálcio/metabolismo , Proliferação de Células , Células Endoteliais/patologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Hipóxia/complicações , Hipóxia/metabolismo , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Artéria Pulmonar/patologia , Retículo Sarcoplasmático/metabolismo , Retículo Sarcoplasmático/patologia , Proteína X Associada a bcl-2/metabolismo
19.
J Thorac Dis ; 10(6): 3232-3243, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30069319

RESUMO

Background: Chronic obstructive pulmonary disease (COPD) is a chronic lung disease with limited treatment options. Hydrogen (H2) has been shown to be anti-oxidative and anti-inflammatory. This study aimed to evaluate the beneficial effects of H2 inhalation on COPD development in mice. Methods: A COPD mouse model was established in male C57BL mice by cigarette smoke (CS) exposure. The H2 intervention was administered by atomisation inhalation. Lung functions were assessed by using Buxco lung function measurement system. The inflammatory cells were counted and the levels of IL-6 and KC in BALF were assayed with ELISA. The lung tissue was subjected to H&E or PAS or Masson's trichrome stain. Furthermore, 16HBE cells were used to evaluate the effects of H2 on signaling change caused by hydrogen peroxide (H2O2). H2O2 was used to treat 16HBE cells with or without H2 pretreatment. The IL-6 and IL-8 levels in cell culture medium were measured. The levels of phosphorylated ERK1/2 and nucleic NF-κB in lungs and 16HBE cells were determined. Results: H2 ameliorated CS-induced lung function decline, emphysema, inflammatory cell infiltration, small-airway remodelling, goblet-cell hyperplasia in tracheal epithelium and activated ERK1/2 and NF-κB in mouse lung. In 16HBE airway cells, H2O2 increased IL-6 and IL-8 secretion in conjunction with ERK1/2 and NF-κB activation. These changes were reduced by H2 treatment. Conclusions: These findings demonstrated that H2 inhalation could inhibit CS-induced COPD development in mice, which is associated with reduced ERK1/2 and NF-κB-dependent inflammatory responses.

20.
Exp Physiol ; 103(11): 1532-1542, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30070749

RESUMO

NEW FINDINGS: What is the central question of this study? In this study, by using motor vehicle exhaust (MVE) exposure with or without lipopolysaccharide (LPS) instillation, we established, evaluated and compared MVE, LPS and MVE+LPS treatment-induced chronic obstructive pulmonary disease (COPD) models in mice. What is the main finding and its importance? Our study demonstrated that the combination of chronic exposure to MVE with early LPS instillation can establish a mouse model with some features of COPD, which will allow researchers to investigate the underlying molecular mechanisms linking air pollution and COPD pathogenesis. ABSTRACT: Although it is well established that motor vehicle exhaust (MVE) has a close association with the occurrence and exacerbation of chronic obstructive pulmonary disease (COPD), very little is known about the combined effects of MVE and intermittent or chronic subclinical inflammation on COPD pathogenesis. Therefore, given the crucial role of inflammation in the development of COPD, we wanted to establish an animal model of COPD using both MVE exposure and airway inflammation, which could mimic the clinical pathological changes observed in COPD patients and greatly benefit the study of the molecular mechanisms of COPD. In the present study, we report that mice undergoing chronic exposure to MVE and intratracheal instillation of lipopolysaccharide (LPS) successfully established COPD, as characterized by persistent air flow limitation, airway inflammation, inflammatory cytokine production, emphysema and small airway remodelling. Moreover, the mice showed significant changes in ventricular and vascular pathology, including an increase in right ventricular pressure, right ventricular hypertrophy and remodelling of pulmonary arterial walls. We have thus established a new mouse COPD model by combining chronic MVE exposure with early intratracheal instillation of LPS, which will allow us to study the relationship between air pollution and the development of COPD and to investigate the underlying molecular mechanisms.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Lipopolissacarídeos/efeitos adversos , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Animais , Modelos Animais de Doenças , Camundongos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia
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